Design, synthesis, and structure–activity relationship study of novel plinabulin derivatives as anti-tumor agents based on the co-crystal structure

Plinabulin, a 2, 5-diketopiperazine-type tubulin inhibitor derived from marine natural products, is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and chemotherapy-induced neutropenia (CIN). To obtain novel 2, 5-diketopiperazine derivatives with higher biological activity, we designed and synthesized two series of 37 plinabulin derivatives at the C-ring, based on the co-crystal structure of compound 1 and tubulin. Their structures were characterized using NMR and HRMS. All compounds were screened in vitro using the lung cancer cell line NCI-H460 using the MTT method, and the compounds with better activity were further screened in BxPC-3 and HT-29 cells. The compounds 16c (IC₅₀ = 2.0, NCI-H460; IC₅₀ = 1.2 nM, BxPC-3; IC₅₀ = 1.97 nM, HT-29) and 26r (IC₅₀ = 0.96, NCI-H460; IC₅₀ = 0.66 nM, BxPC-3; IC₅₀ = 0.61 nM, HT-29) had the best activity. The cytotoxic activity of compound 26r against various tumor cell lines occurred at less than 1 nM.